Process for the preparation of ketimines

ABSTRACT

The present invention relates to a process for the preparation of compounds of formula (1), in which R 1 , R 2  and R 3  independently of one another are hydrogen, halogen , trifluoromethyl of or C 1 -C 4 alkoxy, wherein a compound of formula (2), in which R 1 , R 2  and R 3  are as defined in formula (1), is reacted with methlyamine in the presence of a non-alcoholic solvent and, if desired, in the presence of a sulfonic acid catalyst to give the compound of formula (2) and, if desired, is subject to purification by recrystallization.

This application is 371 of PCT/EP00/10971 filed Nov. 17, 2000.

The present invention relates to a process for the preparation ofketimines, which are suitable as starting materials for the preparationof pharmaceutical active compounds having antidepressant properties, forexample sertraline.

Processes for the preparation of ketimines are described, for example,in U.S. Pat. No. 4,536,518 or U.S. Pat. No. 4,855,600.

The process for the preparation of ketimines disclosed in U.S. Pat No.4,536,518 (columns 9/10, Example 1(F)) is characterized in that theketone is reacted with methylamine with cooling in the presence oftitanium tetrachloride in an aprotic solvent, for exampletetrahydrofuran. This process has the disadvantage that it has to becarried out using titanium tetrachloride, which is ecologicallyhazardous. The process procedure is additionally expensive, because thereaction is carried out with cooling. A further disadvantage of thisprocess relates to the work-up. The product must be precipitated usingadditional hexane.

The process for the preparation of ketimines disclosed in U.S. Pat No.4,855,500 (columns 5/6, claim 1) comprises reacting the ketone withanhydrous methylamine with cooling in an aprotic solvent, such as, forexample, methylene chloride, toluene or tetrahydrofuran in the presenceof a molecular sieve.

This process has the disadvantage that the molecular sieve employed isexpensive and has to be recycled again in an additional step. A furtherdisadvantage of this process is that the molecular sieve has to beseparated off and the product precipitated using additional hexane.

There is therefore furthermore the need to find an efficient process forthe preparation of ketimines, which does not have the abovementioneddisadvantages.

The present invention therefore relates to a process for the preparationof compounds of the formula

in which

R₁, R₂ and R₃ independently of one another are hydrogen, halogen,trifluoromethyl or C₁-C₄alkoxy, wherein a compound of the formula

in which

R₁, R₂ and R₃ are as defined in formula (1) is reacted with methylaminein the presence of a C₁-C₂₄amine or C₁-C₁₂nitrile as solvent to give thecompound of the formula (1), or

is reacted with methylamine in the presence of a sulfonic acid catalystand of a non-alcoholic solvent to give the compound of the formula (1).

Halogen is, for example, chlorine, bromine or iodine. Chlorine ispreferred.

C₁-C₄alkoxy is a branched or unbranched hydrocarbon radical, for examplemethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy ortert-butoxy. Methoxy is preferred.

The non-alcoholic solvent preferred for the process according to theinvention is preferably selected from

(a) C₁-C₂₄amines,

(b) C₁-C₁₂nitriles,

(c) C₂-C₂₄carboxylic acid esters,

(d) C₃-C₂₄orthoesters,

(e) C₂-C₂₄ethers,

(f) C₆-C₂₄alkanes,

(g) aromatic solvents,

(h) amides,

(i) sulfoxides,

(k) halogenated solvents, and

(j) supercritical CO₂.

Particularly preferred solvents (a) are selected from aliphaticmonoamines, in particular methylamine, nitrogen heterocycles, aliphaticdi- and triamines, non-substituted or substituted aromatic monoamines oraromatic diamines.

Further preferred solvents (a) are those of the formula

in which

R₃ is hydrogen; C₁-C₅alkyl; hydroxy-C₁-C₅alkyl; C₅-C₇cycloalkyl; phenylwhich is not substituted or is substituted by one or more C₁-C₅alkylgroups, halogen or nitro; phenyl-C₁-C₃alkyl which is not substituted oris substituted by one or more C₁-C₅alkyl groups, halogen or nitro;

R₄ and R₅, independently of one another, are C₁-C₅alkyl;hydroxy-C₁-C₅alkyl; C₅-C₇cycloalkyl; phenyl which is not substituted oris substituted by one or more C₁-C₅alkyl groups, halogen or nitro;phenyl-C₁-C₃alkyl which is not substituted or is substituted by one ormore C₁-C₅alkyl groups, halogen or nitro; or

R₄ and R₅ together with the nitrogen atom form a three- to 6-memberedheterocyclic radical.

Furthermore, solvents (a) are preferably used which are those of theformula

in which

R₆ and R₈ independently of one another are hydrogen; C₁-C₅akyl; orC₅-C₇cycloalkyl, R₇ and R₉ independently of one another are C₁-C₅alkyl;or C₅-C₇cycloalkyl, phenyl which is not substituted or is substituted byone or more C₁-C₅alkyl groups, halogen or nitro; phenyl-C₁-C₃alkyl whichis not substituted or is substituted by one or more C₁-C₅alkyl groups,halogen or nitro; or

R₆ and R₇, R₈ and R₉ or R₇ and R₉ form a three- to 6-memberedheterocyclic radical; and A₂ is C₁-C₅alkylene.

Exemplary representatives of solvents (a) used according to theinvention which may be mentioned are:

as aliphatic monoamines, for example, methylamine, dimethylamine,triethylamine, diethylamine, triethylamine, di-n-propylamine,diisopropylamine, tri-n-propylamine, or triisopropylamine;

as nitrogen heterocycles ethyleneimine, pyrrolidine, piperidine ormorpholine,

as aliphatic diamines, for example, N,N-dimethylethylenediamine orhexamethylenediamine;

as aromatic monoamines, for example, N-methylaniline orN,N-dimethylaniline;

as substituted aromatic monomamines, for example, o-, m- or p-toluidine,2-, 3- or

4-chloroaniline, 2-, 3- or 4-nitroaniline;

as aromatic diamines, for example, o-, m- or p-phenylenediamine.

Solvents (b) preferably used are those of the formula

in which

R₁₀ is straight-chain or branched C₁-C₁₂alkyl; C₅-C₇cycloalkyl; phenylwhich is not substituted or is substituted by one or more C₁-C₅akylgroups, halogen or nitro; phenyl-C₁-C₃alkyl which is not substituted oris substituted by one or more C₁-C₅alkyl groups, halogen or nitro.

Exemplary representatives of this group are benzonitrile or inparticular acetonitrile. Solvents (c) which are preferably used arecompounds of the formula

in which

R₁₂ and R₁₃ independently of one another are straight-chain or branchedC₁-C₁₂alkyl; C₅-C₇cycloalkyl; or phenyl which is not substituted or issubstituted by one or more C₁-C₅alkyl groups, halogen or nitro;phenyl-C₁-C₃alkyl which is not substituted or is substituted by one ormore C₁-C₅alkyl groups, halogen or nitro.

Exemplary representatives of these solvents are acetates, such as, forexample, methyl acetate or ethyl acetate.

Solvents (d) preferably employed according to the invention are those ofthe formula

in which

R₁₄ is hydrogen; straight-chain or branched C₁-C₅alkyl; orC₅-C₇cycloalkyl; and

R₁₅ is C₁-C₅alkyl.

Exemplary representatives of these solvents are C₁-C₃alkylorthoformates, in particular methyl or ethyl orthoformate or C₁-C₃alklyorthoacetates, in particular ethyl orthoacetate. Solvents (e) preferablyemployed according to the invention are those of the formula

R₁₆—O—R₁₇, in which (8)

R₁₆ and R₁₇ independently of one another are hydrogen; straight-chain orbranched C₁-C₁₂alkyl; or C₅-C₇cycloalkyl; or R₁₆ and R₁₇ together withthe oxygen atom form a 5- to 6-membered radical.

Exemplary representatives of those solvents are dimethyl ether, diethylether, methyl ethyl ether, methyl n-propyl ether, methyl i-propyl ether,diisopropyl ether, dibutyl ether or tert-butyl methyl ether. Inaddition, polyethers can also be employed.

Solvents (f) preferably employed according to the invention aresaturated C₁-C₂₂hydro-carbons, such as, for example, methane, ethane,propane, butane, pentane, hexane, neohexane, heptane, octane, i-octane,nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane,hexadecane, heptadecane, octadecane, nonadecane, eicosane, heneicosaneor docosane.

Solvents (g) preferably employed according to the invention are inparticular benzene, toluene, xylene and xylene isomer mixtures.

Solvents (h) preferably employed according to the invention are inparticular aliphatic and aromatic amides of the formula

in which

R₁₈ and R₁₉ independently of one another are hydrogen; C₁-C₅alkyl; orC₅-C₇cycloalkyl, and

R₂₀ is C₁-C₅alkyl; C₅-C₇cycloalkyl; phenyl which is not substituted oris substituted by one or more C₁-C₅alkyl groups, halogen or nitro; orphenyl-C₁-C₃alkyl which is not substituted or is substituted by one ormore C₁-C₅alkyl groups, halogen or nitro.

Exemplary solvents (i) are those of the formula

R₂₁—(S═O)—R₂₂, in which  (10)

R₂₁, and R₂₂ independently of one another are C₁-C₅alkyl;C₅-C₇cyclalkyl; phenyl which is not substituted or which is substitutedby one or more C₁-C₅alkyl groups, halogen or nitro; or phenyl-C₁-C₃alkylwhich is not substituted or which is substituted by one or moreC₁-C₅alkyl groups, halogen or nitro.

Exemplary solvents (k) are those of the formula

ClCR₂₃R₂₄R₂₅,  (11a)

Cl₂CR₂₆R₂₇ or  (11b)

Cl₃-CR₂₈,in which  (11c)

R₂₃, R₂₄, R₂₅, R₂₆, R₂₇ and R₂₈ independently of one another areC₁-C₅alkyl; C₅-C₇cycloalkyl; phenyl which is not substituted or which issubstituted by one or more C₁-C₅alkyl groups, halogen or nitro; orphenyl-C₁-C₃alkyl which is not substituted or which is substituted byone or more C₁-C₅alkyl groups, halogen or nitro.

Exemplary representatives of this solvent class are dichloroethane,dichloropropane, trichloroethane, furthermore haloaromatics, for examplechlorobenzene or dichlorobenzene.

If supercritical CO₂ is used, the reaction is carried out attemperatures T≧T_(crit) and p≧p_(crit) in CO₂ as solvent. After thereaction, CO₂ is evaporated and the imine is discharged as solid.

The solvents employed according to the invention can be used asindividual compounds or as mixtures of two or more individual compoundsof identical or different solvent groups a)-(l).

In addition, there is the possibility of adding further solubilizing orsolubility-inhibitng additives (e.g. toluene or cyclohexane)

If the preparation of the compound of the formula (1) is carried outwith methylamine in the presence of a C₁-C₂₄ amine or C₁-C₁₂nitrile assolvent (with or without catalyst), the conditions and preferencesindicated above for the solvent (a) apply for the C₁-C₂₄amines and thoseindicated above for the solvent (b) apply for the C₁-C₁₂nitriles. Theuse of solvents (b) is preferred here.

Generally, the use of solvents (a) or (b), in particular (b), ispreferred.

Suitable sulfonic acid catalysts are, for example, methanesulfonic acid,p-toluenesulfonic acid or camphor-10-sulfonic acid.

A process for the preparation of compounds of the formula (1) isespecially preferred in which a sulfonic acid catalyst is used, inparticular p-toluenesulfonic acid, methanesulfonic acid orcamphor-10-sulfonic acid.

The molar quantitative ratio of the catalyst employed to the methylamineemployed is expediently 0.001:1 to 1:1, in particular 0.01:1 to 0.5:1,e.g. 0.05:1 to 0.1:1.

The 1:1 molar quantitative ratio of the catalyst to the methylamine alsomeans that the methylamine can also be employed in the process accordingto the invention in the form of a salt, for example of methylaminehydrochloride.

The process according to the invention is preferably carried out at atemperature from 20 to 120, in particular 30 to 100° C., if appropriateunder slight pressure, and the isolation at a temperature from −20 to40, in particular 0 to 30° C.

For the preparation of the compound of the formula (1) in the presenceof a catalyst, a temperature range from 30 to 80° C., in particular 30to 70° C. and preferably 30 to 60° C., is preferred.

For the preparation of the compound of the formula (1) without thepresence of a catalyst, a temperature range from 50 to 120° C., inparticular 70 to 120° C. and preferably 80 to 120° C., is preferred. Theupper value of the temperature range preferred here is 110° C., inparticular 100° C.

The proportion of sertralone in the reaction mixture is, for example, inthe range from 5 to 70, preferably 30 to 60, % by weight.

The reaction is particularly preferably carried out using a large molarexcess of methylamine.

A process for the preparation of compounds of the formula (1) istherefore particularly preferred in which the molar quantitative ratioof the compound of the formula (2) to methylamine is 1:1 to 1:1000, inparticular 1:1.05 to 1:50, e.g. 1:1.5 to 1:15.

The methylamine can be employed in the form of methylamine gas or as asolution in a non-alcoholic solvent.

A process variant is of very particular interest in which the reactioncan be carried out in pure methylamine, in particular under pressure,this compound being employed simultaneously as a solvent and reagent. Inthis case, customarily no significant amounts of further solvent areemployed.

Also of particular interest is a process for the preparation ofcompounds of the formula (1) in which the compound of the formula (1) iscontinuously crystallized from the reaction medium during thepreparation and then filtered off.

Also of especial interest is a process for the preparation of compoundsof the formula (1), in which the filtrate is employed for a furtherreaction for the preparation of compounds of the formula (1). In thiscase, the amounts of the compound of the formula (2) and methylamineused are replenished. 2 to 10 recyclings of the filtrate are preferred.

The present process according to the invention is accordingly alsosuitable as a continuous process for the preparation of the compounds ofthe formula (1).

The water formed during the process can be bound, if desired, using anadditional chemical water-binding agent for example an orthoester, e.g.trimethyl orthoformate.

After reaction is complete, if desired, the compound of the formula (1)obtained can be subjected to purification by recrystallization.

Preferably, for this purification process a solvent is employed which isselected from

(a) C₁-C₂₄amines,

(b) C₁-C₁₂nitriles,

(c) C₂-C₂₄carboxylic acid esters,

(d) C₃-C₂₄orthoesters,

(e) C₂-C₂₄ethers,

(f) C₆-C₂₄alkanes,

(g) aromatic solvents,

(h) amides,

(i) sulfoxides,

(k) halogenated solvents,

(l) supercritical CO₂,

(m) protic solvents, and

(n) C₂-C₂₄ketones.

The solvents (a) to (l) are the solvents which are also used for thereaction.

The protic solvent (m) is preferably an alcohol, which in particular isof the formula

 X(OH)_(b)  (12)

in which

b is 1, 2, 3 or 4, and

if b is 1,

X is C₁-C₈alkyl, C₅-C₈cycloalkyl or —CH₂CH₂(OCH₂CH₂)_(c)R₂₁,

0, 1 or 2, and

R₂, is C₁-C₄alkoxy, or

if b is 2,

X is C₂-C₈alkylene or —CH₂CH₂(OCH₂CH₂)_(c)—, where c has the abovemeaning, or

if b is 3,

X is C₃-C₈alkanetriyl or N(CH₂CH₂)₃, or

if b is 4,

X is C₄-C₈alkanetetrayl.

In the abovementioned definitions of the radicals R₁ to R₂₁:

C₁-C₁₂alkyl is a branched or unbranched hydrocarbon radical, for examplemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3dimethylbutyl,n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1,1,3,3 tetramethylbutyl,1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, isooctyl, nonyl,decyl, undecyl or dodecyl.

C₅-C₈cycloalkyl is, for example, cyclopentyl, cycloheptyl, cyclooctyl orpreferably cyclohexyl.

C₁-C₄alkoxy is a branched or unbranched hydrocarbon radical, for examplemethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy ortert-butoxy. Methoxy is preferred.

C₂-C₁₂alkenyl is, for example, allyl, methallyl, isopropenyl, 2-butenyl,3butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methylbut-2enyl,n-oct-2-enyl, n-dodec-2-enyl, isododecenyl, n-dodec-2-enyl orn-octadec-4-enyl.

C₃-C₁₂alkynyl is C₃-C₁₂alkyl or C₃-C₁₂alkenyl, which is mono- orpolydiunsaturated, where the triple bonds can, if desired, be isolatedor conjugated with one another or with double bonds, for example1-propyn-3-yl, 1-butyn-4-yl, 1-pentyn-5-yl, 2-methyl-3-butyn-2-yl,1,4-pentadiyn-3-yl, 1,3-pentadiyn-5-yl, 1-hexyn-6-yl,cis-3-methyl-2-penten-4-yn-1-yl, trans-3-methyl-2-pentyn-4-yn-1 -yl,1,3-hexadiyn-5-yl, 1-octy-8-yl, 1-nonyn-9-yl or 1-decyn-10-yl.

C₂-C₈alkylene is a branched or unbranched radical, for example ethylene,propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene or octamethylene.

Alkanetriyl having 3 to 8 carbon atoms is derived, for example, from analkane having 3 to 8 carbon atoms, in which 3 hydrogen atoms are absentand is, for example

Glyceryl is preferred.

Alkanetetrayl having 4 to 8 carbon atoms is derived, for example, froman alkane having 4 to 8 carbon atoms, in which 4 hydrogen atoms areabsent, and is, for example

Pentaerythrityl is preferred.

A preferred meaning of X (for b=1) is, for example, C₁-C₆alkyl, inparticular C₁-C₄alkyl, e.g. ethyl or isopropyl.

A preferred meaning of X (for b=2) is, for example, C₂-C₆alkylene, inparticular C₂-C₄alkylene, e.g. ethylene.

Of particular interest is a process for the preparation of compounds ofthe formula (1), in which the protic solvent is a compound of theformula (12), in which

b is 1 or 2, and

if b is 1,

X is C₁-C₄alkyl or C₅-C₆cycloalkyl, or

if b is2,

X is C₂-C₄alkylene.

Practically relevant alcohols for the purification step are methanol,ethanol, isopropanol, n-butanol, ethylene glycol, methylcellosolve,cyclohexanol, diethylene glycol or triethanolamine.

Solvents employed for the purification process are furthermoreC₂-C₂₄ketones (=Component (n)), which in particular are those of theformula

in which

R₂₂ and R₂₃ independently of one another are branched or unbranchedC₁-C₁₂alkyl; C₅-C₇cycloalkyl; C₂-C₁₂alkenyl; C₃-C₁₂alkynyl; phenyl orphenyl-C₁-C₃alkyl, which is not substituted or is substituted by one ormore C₁-C₅alkyl groups;

A₁ is a direct bond; or C₁-C₅alkylene; and n is 0 or 1.

Exemplary representatives of this group are, for example, aliphaticallysaturated ketones, such as, for example, propanone (acetone), butanone(methyl ethyl ketone) or 2-pentanone (methyl propyl ketone);cycloaliphatically saturated ketones, for example cyclopentanone,cyclohexanone or cycloheptanone (suberone); aliphatically unsaturatedketones, for example 3buten-2-one, 1,4-pentadien-3-one, 3-pentyn-2-one;aromatic ketones, for example benzophenone; aromatic/aliphatic ketones,for example methyl phenyl ketone (acetophenone) or propiophenone;diketones, for example 2,3-butanedione, 2,4-pentanedione or2,5-hexanedione; or aromatic diketones, for example diphenylethanedione(benzil).

In a particularly preferred embodiment, the purification is carried outin the same solvent as the reaction.

In a preferred process variant, the purification is carried out byrecrystallization of sertraline (compound of the formula (1)) underreflux. For this, the isomerically pure sertraline is introduced in asuitable solvent into a suitable reaction vessel having a stirrer andreflux condenser. The reaction mass is heated to reflux temperature inan inert gas atmosphere with stirring until a clear solution is present.The solution is cooled to the appropriate isolation temperature, theproduct slowly crystallizing. The suspension is filtered, and the filtercake is washed with the solvent and dried. The imine yield is from 80 to99%, with a sertralone content of 0.1 to 5.0% (HPLC), a catalystcontamination of≦0.01 and up to 0.3% water content.

In a further process variant, the recrystallization of sertraline iscarried out under pressure. For this, the crude sertraline and thesolvent are introduced into a suitable pressure reactor having astirrer. The reactor is sealed under a nitrogen atmosphere. The stirreris started and the reaction mixture is heated to the desired reactiontemperature until a clear solution is present. The solution is cooled tothe appropriate isolation temperature, the product slowly precipitating.The suspension is filtered, and the filter cake is washed with thesolvent and dried.

The solution temperatures in the selected solvents are in the range from30 to 150, preferably 70 to 120° C.

According to the boiling points of the solvents indicated, thepurification process can be carried out at normal pressure under refluxor at elevated pressure, normally in the range from 0 to 10, preferablyfrom 0 to 3, bar.

The cooling gradients are in the range from 0.05 to 10, preferably 0.1to 1, ° C./min.

The isolation temperatures are in the range from −20 to 40, preferably 0to 25, ° C.

The concentrations of crude sertraline in the clear solution are in therange from 5 to 40, preferably 15 to 20, % by weight.

During the process, adsorbents, for example active carbon or adsorberresins, can be added for the removal of colouring impurities. Theseadsorbents are added to the clear solution in amounts from 1 to 10% andremoved hot by filtration before the crystallization process.

By means of the purification step, both the product purity can beimproved and impurities interfering in the further reaction, for examplewater or catalyst residues, can be separated off.

In a very particularly preferred embodiment, the reaction according toclaim 1 is carried out in the presence of a sulfonic acid catalyst andthe compound of the formula (1 ) obtained is subjected to a purificationstep.

The present invention also relates to a process for the preparation ofoptically pure (cis) and/or (trans)-sertraline or enantiomericallyenriched mixtures of (cis)- and (trans)-sertraline. The process ischaracterized by the following reaction steps (I)-(III):

(I) reaction of pure sertralone of the formula (2) to give thesertraline of the formula (1) corresponding to the process according toclaim 1,

(II) subsequent cis-selective hydrogenation with noble metal catalystsor other catalysts based on copper or nickel to givecis-sertraline-enriched mixtures of racemic cis- and trans-sertraline,

(III) subsequent mandelic acid-based resolution for the selectivepreparation of the desired enantiomerically pure cis isomer.

Starting from pure sertralone, sertraline is prepared according to theprocess described in claim 1. The imine is converted tocis-sertraline-enriched mixtures of racemic cis- and trans-sertraline ina subsequent cis-selective hydrogenation with noble metal catalysts orother catalysts based on copper or nickel on very different supports,such as, for example, carbon, alumina, silica, calcium carbonate, bariumcarbonate, barium sulfate etc.

In a subsequent mandelic acid-based resolution, the desiredenantiomerically pure cis isomers can be crystallized.

The optically pure amine is liberated using sodium hydroxide solutionand converted into the desired polymorphic form as the hydrochloride insuitable solvents.

The following examples illustrate the invention further. Details inparts or percentages relate to the weight.

EXAMPLE 1 Preparation of Sertraline in Acetonitrile with Acid Catalysis

240 g of pure sertralone (>99%) and 650 ml of acetonitrile areintroduced into a suitable reaction vessel having a stirrer and gasinlet. The stirrer is started, the suspension is cooled to 0° C. and 55g of methylamine are passed in. After addition of 10 ml ofmethanesulfonic acid (catalyst), the reaction mass is heated, stirred at50° C. until the reaction stops and then cooled to 0° C. The suspensionis filtered, washed with cold acetonitrile and dried in vacuo.

Yield: 231.4 g (corresponds to 92.5% of theory) of crude sertralinehaving the following composition:

96.6% sertraline;

2.9% sertralone;

0.5% water.

The product additionally contains traces of methanesulfonic acidderivatives and salts.

EXAMPLE 2 Preparation of Sertraline in Amines with Acid Catalysis at 50°C.

10 g of pure sertralone (>99%) and 23 g of amine are introduced into asuitable reaction vessel having a stirrer and gas inlet The stirrer isstarted, the suspension is cooled to 0° C. and 3 g of methylamine arepassed in. After addition of 0.65 g (0.1 eq) of para-toluene-sulfonicacid (catalyst), the reaction mass is heated to 50° C., stirred untilthe reaction stops and then cooled to 10° C. The suspension is filtered,washed with cold ethanol and dried in vacuo.

The following yields for various amines as solvents are obtained:

N-Benzyldimethylamine: 9.3 g of sertraline (corresponds to 90% oftheory)

Content:

96% imine,

3.8% sertralone,

0.2% water.

The product additionally contains traces of para-toluenesulfonic acidderivatives.

Triethylamine: 8.8 g of sertraline (corresponds to 85% of theory)

Content:

95% imine,

4.8% sertralone,

0.2% water.

The product additionally contains traces of para-toluenesulfonic acidderivatives.

Diethylamine: 8.9 g of sertraline (corresponds to 86% of theory)

Content:

94% imine,

5.9% sertralone,

0.1% water.

The product additionally contains traces of para-toluenesulfonic acidderivatives.

Diisopropylamine: 7.4 g of sertraline (corresponds to 71% of theory)

Content:

93% imine,

6.9% sertralone,

0.1% water.

The product additionally contains traces of para-toluenesulfonic acidderivatives.

Ethyldiisopropylamine: 85 g of sertraline (corresponds to 82% of theory)

Content:

93% imine,

6.9% sertralone,

0.1% water.

The product additionally contains traces of para-toluenesulfonic acidderivatives.

EXAMPLE 3 Preparation of Sertraline without Acid Catalysis at 90° C.

10 g of pure sertralone (>99%) and 23 g of amine are introduced into asuitable reaction vessel having a stirrer and gas inlet. The stirrer isstarted, the suspension is cooled to 0° C. and 3 g of methylamine arepassed In. The reaction mass is heated, stirred at 90° C. until thereaction stops and then cooled to 10° C. The suspension is filtered,washed with cold ethanol and dried in vacuo.

The following results emerge for various amines as solvents:

N-Benzyldimethylamine: 8.5 g of sertraline (corresponds to 81% oftheory)

Content:

95% imine,

4.8% sertralone,

02% water

Triethylamine: 9.2 9 of sertraline (corresponds to 88% of theory)

Content:

96% imine,

3.8% sertralone,

02% water.

N-Methylpiperzine: 6.4 g of sertraline (corresponds to 61% of theory)

Content:

97% imine,

2.8% sertralone,

0.2% water.

EXAMPLE 4 Preparation of Sertraline in Methylamine Using a Catalyst at60° C.

6 g of pure sertralone (>99%) and 0.5 g of para-toluenesulfonic acid areintroduced into a suitable pressure reaction vessel (autoclave) having astirrer and gas inlet. 24 g of methylamine are then injected. Thestirrer is started. The reaction mass is heated, kept at 60° C. and thencooled to room temperature. The methylamine is released in a controlledmanner and the residual, solid product dried in vacuo.

Yield: 6.9 g of sertraline (corresponds to 99% of theory)

Content:

89% imine,

1% sertralone,

3% water.

7% para-toluenesulfonic acid derivatives.

EXAMPLE 5 Preparation of Sertraline in Methylamine without a Catalyst at90° C.

6 g of pure sertralone (>99%) are introduced into a suitable pressurereaction vessel (autoclave) having a stirrer and gas inlet. 24 g ofmethylamine are then injected. The stirrer is started. The reaction massis heated, kept at 90° C. and then cooled to room temperature. Themethylamine is released in a controlled manner and the residual, solidproduct is dried in vacuo.

Result 6.4 g of sertraline (corresponds to 99% of theory)

Content:

96% imine,

1% sertralone,

3% water.

EXAMPLE 6 Purification of Sertraline in Acetonitrile

200 g of crude sertraline (cf. Example 1) and 3.5 l of acetonitrile areinitially introduced into a suitable reaction vessel having a stirrer,nitrogen inlet and reflux condenser. The nitrogen flushing and thestirrer are started and the reaction mixture is heated to refluxtemperature until a clear solution is present. The solution is slowlycooled to 20° C., the product precipitating. The suspension is filtered,and the filter cake is washed with the solvent and dried.

Yield: 178 g of sertraline having the following composition (GCanalysis):

99.4% sertraline (corresponds to 88.0% of theory),

0.6% sertralone.

Methanesulfonic acid derivatives and salts are no longer detectable.

EXAMPLE 7 Purification of Sertraline in Ethyl Acetate

200 g (0.637 mol) of crude dry sertraline (96.9% purity) are suspendedin 1000 ml of ethyl acetate and 8.0 g of active carbon in a suitablereaction container, equipped with a stirrer and reflux condenser. Themixture is stirred under reflux for 1 h. The active carbon is filteredoff hot and the clear filtrate is cooled to 0° C. The crystallinesuspension is filtered off. The filter cake is dried overnight in vacuoand yields 174 g (89%) of sertraline.

Purity: 99.5%; 0.3% sertralone.

Methanesulfonic acid derivatives and salts are no longer detectable.

EXAMPLE 8 Purification of Sertraline in other Solvents Analogously tothe Previous Examples:

Other solvents and mixtures can also be used for the purification ofcrude sertraline (same conditions as above) and produce a similarproduct purity and yield (cf. Table 1).

The reaction is carried out by heating under reflux.

TABLE 1 Solvent used Yield [%] Purity [%] Sertralone content [%]2-Butanone (MEK) 88 99.4 0.4 Mixture of ethanol/ 90 99.6 0.4 toluene(7:3 vol.) 2-Propanol (IP) 90 99.8 0.4

Pure ethanol or ethanol denatured with 2% toluene can also be used forthe recrystallization of crude sertraline.

The ratio to be employed is: 2 g of crude sertralone in 30 ml ofethanol.

Yield with 86% and 99.4% purity; 0.5% sertralone.

By adjusting the solubility using solubililty-inhibiting compounds suchas alkanes and/or low isolation temperatures, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMAC) and dimethyl sulfoxide (DMSO) canalso be used, which can also be employed pure or in mixtures for theimine formation.

In all solvents used, the catalyst residues are no longer detectableafter the recrystallization.

EXAMPLE 9 Recrystallization of Sertraline above the Boiling Point of theSolvent (Under Pressure)

5 g of crude sertraline (product from Example 2) and 15 to 20 ml ofethanol are introduced into a suitable pressure reaction vessel having astirrer. The reactor is sealed under a nitrogen atmosphere and thestirrer is started. The reaction mixture is heated to about 110° C.until a dear solution is present. The solution is cooled to 25° C., theproduct slowly precipitating. The suspension is filtered, and the filtercake is washed with cold ethanol and dried.

Yield: 4.55 g (91%) of sertraline having the following composition:

99.4% sertraline

0.6% sertralone.

Water and traces of catalyst are no longer detectable.

If ethyl acetate is used instead of ethanol, a yield of 4.35 g (87%) isobtained.

What is claimed is:
 1. A process for the preparation of compounds of theformula

in which R₁, R₂ and R₃ independently of one another are hydrogen,halogen, trifluoromethyl or C₁-C₄alkoxy, wherein a compound of theformula

in which R₁, R₂ and R₃ are as defined in formula (1), is reacted withmethylamine in the presence of a sulfonic acid catalyst and of anon-alcoholic solvent to give the compound of the formula (1).
 2. Aprocess according to claim 1, wherein a compound of the formula (2) isreacted with methylamine in the presence of a C₁-C₂₄amine orC₁-C₁₂nitrile as solvent to give the compound of the formula (1).
 3. Aprocess according to claim 1, wherein the non-alcoholic solvent isselected from (a) C₁-C₂₄amines, (b) C₁-C₁₂nitriles, (c) C₂-C₂₄carboxylicacid esters, (d) C₃-C₂₄orthoesters, (e) C₂-C₂₄ethers, (f) C₆-C₂₄alkanes,(g) aromatic solvents, (h) C₁-C₂₄amides, (i) sulfoxides, (k) halogenatedsolvents, and (l) supercritical CO₂.
 4. A process according to claim 3,wherein the C₁-C₂₄amines used as solvents are methylamine, nitrogenheterocycles, or aliphatic or aromatic non-substituted or substitutedsecondary or tertiary mono-, di- or triamines.
 5. A process according toclaim 4, wherein the C₁-C₂₄amines used are compounds of the formula

in which R₃ is hydrogen; C₁-C₅alkyl; hydroxy-C₁-C₅alkyl;C₅-C₇cycloalkyl; phenyl which is not substituted or is substituted byone or more C₁-C₅alkyl groups, halogen or nitro; phenyl-C₁-C₃alkyl whichis not substituted or is substituted by one or more C₁-C₅alkyl groups,halogen or nitro; R₄ and R₅, independently of one another, areC₁-C₅alkyl; C₅-C₇cycloalkyl; hydroxy-C₁-C₅alkyl; phenyl which is notsubstituted or is substituted by one or more C₁-C₅alkyl groups, halogenor nitro; phenyl-C₁-C₃alkyl which is not substituted or is substitutedby one or more C₁-C₅alkyl groups, halogen or nitro; or R₄ and R₅together with the nitrogen atom form a 3- to 6-membered heterocyclicradical.
 6. A process according to claim 4, wherein the C₁-C₂₄aminesused are compounds of the formula

in which R₆ and R₈ independently of one another are hydrogen;C₁-C₅alkyl; or C₅-C₇cycloalkyl, R₇ and R₉ independently of one anotherare C₁-C₅alkyl; or C₅-C₇cycloalkyl, phenyl which is not substituted oris substituted by one or more C₁-C₅alkyl groups, halogen or nitro;phenyl-C₁-C₃alkyl which is not substituted or is substituted by one ormore C₁-C₅alkyl groups, halogen or nitro; or R₆ and R₇, R₈ and R₉ or R₇and R₉ form a 3- to 6-membered heterocyclic radical; and A₂ isC₁-C₅alkylene.
 7. A process according to claim 3, wherein theC₁-C₁₂nitriles used as solvents are compounds of the formula

in which R₁₀ is straight-chain or branched C₁-C₁₂alkyl; C₅-C₇cycloalkyl;phenyl which is not substituted or is substituted by one or moreC₁-C₅alkyl groups, halogen or nitro; phenyl-C₁-C₃alkyl which is notsubstituted or is substituted by one or more C₁-C₅alkyl groups, halogenor nitro.
 8. A process according to claim 3, wherein the solvents (c)used are compounds of the formula

in which R₁₂ and R₁₃ independently of one another are straight-chain orbranched C₁-C₁₂alkyl; C₅-C₇cycloalkyl; or phenyl which is notsubstituted or is substituted by one or more C₁-C₅alkyl groups, halogenor nitro; phenyl-C₁-C₃alkyl which is not substituted or is substitutedby one or more C₁-C₅alkyl groups, halogen or nitro.
 9. A processaccording to claim 3, wherein the solvents (d) used are compounds of theformula

in which R₁₄ is hydrogen; straight-chain or branched C₁-C₅alkyl; orC₅-C₇cycloalkyl; and R₁₅ is C₁-C₅akyl.
 10. A process according to claim3, wherein the solvents (e) used are compounds of the formula R₁₆—O—R₁₇,in which  (8) R₁₆ and R₁₇ independently of one another are hydrogen;straight-chain or branched C₁-C₁₂alkyl; or C₅-C₇cycloalkyl; or R₁₆ andR₁₇ together with the oxygen atom form a 5- to 6membered radical.
 11. Aprocess according to claim 3, wherein the solvents (f) used aresaturated C₁-C₂₂hydrocarbons.
 12. A process according to claim 3,wherein the solvents (g) are selected from benzene, toluene, xylene andxylene isomer mixtures.
 13. A process according to claim 1, wherein thecompound of the formula (1) is recrystallized from the reaction mediumcontinuously during the preparation and then filtered off.
 14. A processaccording to claim 13, wherein the filtrate is employed for a furtherreaction for the preparation of the compound of the formula (1).
 15. Aprocess according to claim 1, wherein the molar quantitative ratio ofthe compound of the formula (2) to methylamine is 1:1 to 1:1000.
 16. Aprocess according to claim 1, wherein the reaction is carried out at atemperature from 20 to 120° C. and the isolation is carried out at atemperature from −20° C. to 40° C.
 17. A process according to any one ofclaims 1 to 16, wherein the reaction is carried out at elevatedpressure.
 18. A process according to claim 1, wherein the sulfonic acidcatalyst is p-toluenesulfonic acid, methanesulfonic acid orcamphor-10-sulfonic acid.
 19. A process according to claim 1, whereinthe compound of the formula (1) obtained is subjected to purification byrecrystallization using a solvent.
 20. A process according to claim 19,wherein the solvent is selected from (a) C₁-C₂₄amines, (b)C₁-C₁₂nitriles, (c) C₂-C₂₄carboxylic acid esters, (d) C₃-C₂₄orthoesters,(e) C₂-C₂₄ethers, (f) C₆-C₂₄alkanes, (g) aromatic solvents, (h) amides,(i) sulfoxides, (k) halogenated solvents, (i) supercritical CO₂, (m)protic solvents, and (n) C₂-C₂₄ketones.
 21. A. A process according toclaim 20, wherein the protic solvent (m) is an alcohol.
 22. A processaccording to claim 20, wherein the protic solvent (m) is selected frommethanol, ethanol, isopropanol, n-butanol, ethylene glycol,methylcellosolve, cyclohexanol, diethylene glycol, triethanolamine andpolyethylene glycol.
 23. A process according to claim 20, wherein thesolvent(s) are selected from compounds of the formula

in which R₂₂ and R₂₃ independently of one another are branched orunbranched C₁-C₁₂alkyl; C₅-C₇cycloalkyl; C₂-C₁₂alkenyl; C₃-C₁₂alkynyl;phenyl or phenyl-C₁-C₃alkyl, which is not substituted or is substitutedby one or more C₁-C₅alkyl groups; A₁ is a direct bond; or C₁-C₅alkylene;and n is 0 or
 1. 24. A process according to claim 19, wherein thepurification is carried out in the same solvent as the reaction itself.25. A process according to claim 19, wherein the purification is carriedout under reflux.
 26. A process according to claim 19, wherein thepurification is carried out at elevated pressure.
 27. A processaccording to claim 19, wherein the purification is carried out at atemperature of≦150° C.
 28. A process according to claim 19, wherein thecooling gradient is in the range from 0.05 to 10° C./min.
 29. A processaccording to claim 19, wherein the isolation temperature is in the rangefrom −20 to 40° C.
 30. A process according to claim 19, wherein therecrystallization is carried out at elevated pressure.
 31. A processaccording to claim 1, wherein the reaction is carried out in thepresence of a sulfonic acid catalyst and the compound of the formula (1)obtained is subjected lo a purification step.
 32. A process according toclaim 1, wherein the starting compound of the on has a purity of>99%.33. A process for the preparation of optically pure (cis)- and/or(trans)-sertraline or enantiomerically enriched mixtures of (cis)- and(trans)-sertraline, which comprises the following reaction steps(I)-(III): (I) reaction of pure sertralone of the formula (2) to givethe sertraline of the formula (1) according to the process according toclaim 1, (II) subsequent cis-selective hydrogenation with noble metalcatalyst or other catalysts based on copper or nickel to givecis-sertraline-enriched mixtures of racemic cis- and trans-sertraline,and (III) subsequent mandelic acid-based resolution for the selectivepreparation of the desired enantiomerically pure cis isomer.